Frontiers in Cell and Developmental Biology (Feb 2022)
Adenosine Kinase Inhibition Prevents Severe Acute Pancreatitis via Suppressing Inflammation and Acinar Cell Necroptosis
- Shukun Sun,
- Shukun Sun,
- Shukun Sun,
- Shukun Sun,
- Yu Han,
- Yu Han,
- Yu Han,
- Yu Han,
- Chuanxin Zhang,
- Chuanxin Zhang,
- Chuanxin Zhang,
- Chuanxin Zhang,
- Han Liu,
- Han Liu,
- Han Liu,
- Han Liu,
- Bailu Wang,
- Shengchuan Cao,
- Shengchuan Cao,
- Shengchuan Cao,
- Shengchuan Cao,
- Qiuhuan Yuan,
- Qiuhuan Yuan,
- Qiuhuan Yuan,
- Qiuhuan Yuan,
- Shujian Wei,
- Shujian Wei,
- Shujian Wei,
- Shujian Wei,
- Yuguo Chen,
- Yuguo Chen,
- Yuguo Chen,
- Yuguo Chen
Affiliations
- Shukun Sun
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Shukun Sun
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Shandong University, Jinan, China
- Shukun Sun
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Shukun Sun
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Qilu Hospital, Cheeloo College of Medicine, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Shandong University, Jinan, China
- Yu Han
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Yu Han
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Shandong University, Jinan, China
- Yu Han
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Yu Han
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Qilu Hospital, Cheeloo College of Medicine, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Shandong University, Jinan, China
- Chuanxin Zhang
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Chuanxin Zhang
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Shandong University, Jinan, China
- Chuanxin Zhang
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Chuanxin Zhang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Qilu Hospital, Cheeloo College of Medicine, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Shandong University, Jinan, China
- Han Liu
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Han Liu
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Shandong University, Jinan, China
- Han Liu
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Han Liu
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Qilu Hospital, Cheeloo College of Medicine, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Shandong University, Jinan, China
- Bailu Wang
- Clinical Trial Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Shengchuan Cao
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Shengchuan Cao
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Shandong University, Jinan, China
- Shengchuan Cao
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Shengchuan Cao
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Qilu Hospital, Cheeloo College of Medicine, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Shandong University, Jinan, China
- Qiuhuan Yuan
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Qiuhuan Yuan
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Shandong University, Jinan, China
- Qiuhuan Yuan
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Qiuhuan Yuan
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Qilu Hospital, Cheeloo College of Medicine, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Shandong University, Jinan, China
- Shujian Wei
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Shujian Wei
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Shandong University, Jinan, China
- Shujian Wei
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Shujian Wei
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Qilu Hospital, Cheeloo College of Medicine, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Shandong University, Jinan, China
- Yuguo Chen
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Yuguo Chen
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Shandong University, Jinan, China
- Yuguo Chen
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Yuguo Chen
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Qilu Hospital, Cheeloo College of Medicine, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Shandong University, Jinan, China
- DOI
- https://doi.org/10.3389/fcell.2022.827714
- Journal volume & issue
-
Vol. 10
Abstract
Background: Inflammatory disorder and acinar cell death contribute to the initiation and progression of severe acute pancreatitis (SAP). Adenosine kinase (ADK) has potential effects on both inflammation and cell death. However, the role of ADK in SAP remains to be explored.Methods: To establish an experimental SAP model, male C57BL/6 mice were intraperitoneally injected with cerulein (50 μg/kg, seven doses at hourly intervals) and LPS (10 mg/kg, at the last cerulein injection). For ADK inhibition, ABT702 (1.5 mg/kg) was intraperitoneally injected 1 h before cerulein treatment. The pancreas and serum were collected and analyzed to determine the severity of pancreatic injury and explore the potential pathophysiological mechanisms. Pancreatic acinar cells (AR42J) were used to explore the in vitro effects of ADK inhibition on cerulein–induced inflammation and necroptotic cell death.Results: ADK inhibition notably attenuated the severity of SAP, as indicated by the decreased serum amylase (7,416.76 ± 1,457.76 vs. 4,581.89 ± 1,175.04 U/L) and lipase (46.51 ± 11.50 vs. 32.94 ± 11.46 U/L) levels and fewer pancreatic histopathological alterations (histological scores: 6.433 ± 0.60 vs. 3.77 ± 0.70). MOMA-2 and CD11b staining confirmed that ADK inhibition prevented the infiltration of neutrophils and macrophages. The phosphorylation of nuclear factor-κB (NF-κB) was also reduced by ADK inhibition. ADK inhibition markedly limited the necrotic area of the pancreas and prevented the activation of the necroptotic signaling pathway. Endoplasmic reticulum (ER) stress was activated in the pancreas using the SAP model and cerulein–treated AR42J cells whereas ADK inhibition reversed the activation of ER stress both in vivo and in vitro. Moreover, the alleviating effects of ADK inhibition on ER stress, inflammation, and cell necroptosis were eliminated by the adenosine A2A receptor antagonist.Conclusion: ADK inhibition reduced inflammation and necroptotic acinar cell death in SAP via the adenosine A2A receptor/ER stress pathway, suggesting that ADK might be a potential therapeutic target for SAP.
Keywords
